Phase II Evaluation of Sunitinib Malate, a Multi-Targeted Inhibitor of Receptor Tyrosine Kinases, in Patients with Myelofibrosis.

BACKGROUND: Sunitinib Malate is a small molecule inhibitor of receptor tyrosine kinases (TK) with a broad spectrum of activity against VEGFR-1, -2, and -3, PDGFR-α and -β, c-kit, the TK encoded by the ret oncogene, and Flt-3. As TK-mediated angiogenesis may be an integral element in the pathogenesis and progression of myelofibrosis (MF), we investigated the use of sunitinib in MF patients.

METHODS: 14 patients (pt) have been treated with sunitinib 37.5mg orally daily in six-week cycles, with response assessment after 2 and 4 cycles. Median baseline characteristics (range): age 65 years (50–79); 2 previous therapies (0–4); B-symptoms 64%; Hb < 8g/dL or transfusion-dependent 50%; JAK-2 mutated 57%.

RESULTS: Pt received sunitinib for a median of 101 days (23–173). Six stopped study drug prior to the planned four cycles because of toxicity (5) or disease progression (1); four stopped at four cycles because of toxicity (1) or lack of response (3); one stopped at five cycles because of lack of response; and three patients still on therapy had shown no responses at 3, 3 and 5 cycles. No responses were observed. One patient had 50% reduction in splenomegaly but became transfusion-dependent, and was considered a non-response. Grade 1 or 2 hypertension developed in 7 (50%) patients and was more common in patients with a pre-existing history of hypertension (5/7) than patients without a history of hypertension (2/7); in six patients, hypertension led to interruption and/or dose reduction in study medication. Common toxicities were constitutional (fatigue 86%, Grade 3=21%), gastrointestinal (abdominal pain, nausea or diarrhea 79%, Grade 3=14%) or neurologic (pain or numbness in extremity 43%, Grade 3=0%). Grade 3 bleeding (1 epistaxis, 1 upper GI) occurred in 2 patients, and grade 3 optic disc edema in 1. Toxicities were cumulative and dose-related, with dose reductions being required in 7/10 patients who continued beyond 2 cycles.

CONCLUSIONS: At the first planned interim analysis, no responses were recorded in 14 patients treated with sunitinib. This fulfiled the early stopping rule in the Gehan two-stage study design, and the study has been closed to new patient accrual because of inadequate response.